The immune system is tightly controlled by a network of costimulatory and co-inhibitory ligands and receptors. These molecules provide secondary signals for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection and tumors, while limiting immunity to self (Wang et al., (Epub Mar. 7, 2011) J Exp Med 208(3):577-92; Lepenies et al., (2008) Endocr Metab Immune Disord Drug Targets 8:279-288).
Programmed Death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. The ligand for PD-1, PD-L1, is expressed by antigen-presenting cells and many cancers such as lung, ovarian and colon carcinoma and various myelomas. Binding of PD-L1 to PD-1 on T cells downregulates T cell proliferation and activation and drives T cell anergy and exhaustion in the tumor microenvironment, facilitating tumor cell escape from T-cell mediated immune surveillance.
Therapeutic efficacy of PD-1 and PD-L1 antagonists has been validated in clinical trials. However, response rates remain low. For example, Opdivo® (Nivolumab) treatment achieved a 26% objective response rate (ORR) across the 27 clinical trials analyzed (Tie et al., Int J Cancer 2016 Nov. 4 doi: 10.1002/ijc.30501. [Epub ahead of print])
Measuring the expression of PD-L1 protein in the tumor tissue may aid in the early detection of cancer pathologies and may help assess the efficacy and durability of PD-L1 and PD-1 antagonists. For example, PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of Keytruda® (pembrolizumab) (Garon et al., N Engl J Med 2015; 372:2018-2028), and PD-L1 expression has been correlated with poor prognosis (see for example Wang et al., Eur J Surg oncol 2015 April; 41(4):450-6).
However, the use of PD-L1 protein expression as an accurate predictor for cancer and/or the efficacy of anti-PD-1 and anti-PD-L1 directed therapies remain challenging partially due to observed variability in results depending on the detection reagent used. For example, the evaluation of PD-L1 expression in non-small cell lung cancer samples using commercially available assays such as PD-L1 (E1L3N®) XP® Rabbit mAb (Cell Signaling) and Ventana PD-L1 (SP142) Assay yielded discordant results (McLaughlin et al., JAMA Oncol 2016 January; 2(1):46-54)
Therefore, there is a need for reagents to accurately detect PD-L1 in tumor tissues and other samples and new therapeutics that modulate the interaction between PD-L1 and PD-1.